ABSTRACT
BACKGROUND: Prediction of the response to a biological treatment in psoriasis patients would allow efficient treatment allocation. OBJECTIVE: To identify polymorphisms associated with secukinumab response in psoriasis patients in a daily practice setting. METHODS: We studied 180 SNPs in patients with moderate-to-severe plaque psoriasis recruited from 15 Spanish hospitals. Treatment effectiveness was evaluated by absolute PASI ≤3 and ≤1 at 6 and 12 months. Individuals were genotyped using a custom Taqman array. Multiple logistic regression models were generated. Sensitivity, specificity and area under the curve (AUC) were analysed. RESULTS: A total of 173 patients were studied at 6 months, (67% achieved absolute PASI ≤ 3 and 65% PASI ≤ 1) and 162 at 12 months (75% achieved absolute PASI ≤ 3 and 64% PASI ≤ 1). Multivariable analysis showed the association of different sets of SNPs with the response to secukinumab. The model of absolute PASI≤3 at 6 months showed best values of sensitivity and specificity. Four SNPs were associated with the capability of achieving absolute PASI ≤ 3 at 6 months. rs1801274 (FCGR2A), rs2431697 (miR-146a) and rs10484554 (HLCw6) were identified as risk factors for failure to achieve absolute PASI≤3, while rs1051738 (PDE4A) was protective. AUC including these genotypes, weight of patients and history of biological therapy was 0.88 (95% CI 0.83-0.94), with a sensitivity of 48.6% and specificity of 95.7% to discriminate between both phenotypes. CONCLUSION: We have identified a series of polymorphisms associated with the response to secukinumab capable of predicting the potential response/non-response to this drug in patients with plaque psoriasis.
ABSTRACT
We performed a study to quantify CYP2C9 and CYP2C8 alleles influence on the variability observed in tenoxicam pharmacokinetic (PK) and implication in a bioequivalence study design performed on Spaniards. Eighteen healthy volunteers were included in an open, randomized, crossover, phase I bioequivalence study. Significant increases were found in CYP2C9*3 alleles vs. *1 and *2 in AUC(0-infinity) (median (min-max)): 256 (230-516) vs. 150 (100-268) and 169 (124-197) microg h/mL (p<0.01) and half-life time (t1/2) 102 (79-36) vs. 56 (45-94) and 64 (60-80)h (p<0.01). Non-significant differences were observed in C(max) 1.9 (1.8-2.9) vs. 2.4 (1.7-3.4), 2.5 (1.6-2.9) microg/mL or in according to CYP2C8 alleles presence. CYP2C9*3 allele is associated to a longer elimination time of tenoxicam. PK parameters calculated in bioequivalence studies (AUC(0-infinity), t1/2) may be influenced by the presence of CYP2C9*3 allele resulting in a high variability. Thus, bioequivalence studies of tenoxicam formulations should be designed considering genotype profile.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacokinetics , Aryl Hydrocarbon Hydroxylases/genetics , Piroxicam/analogs & derivatives , Adolescent , Adult , Alleles , Area Under Curve , Cross-Over Studies , Cytochrome P-450 CYP2C9 , Female , Genotype , Humans , Male , Pharmacogenetics , Piroxicam/pharmacokinetics , Spain , Therapeutic EquivalencyABSTRACT
Hepatitis C virus (HCV) infection is the main cause for chronic hepatitis, leading to cirrhosis and hepatic carcinoma. Virally induced immune dysfunction has been called as the cause for viral persistence. Previous results demonstrate that CD4 Jurkat cells stably expressing the HCV core protein show an increased activation of NFAT transcription factor and an impaired IL-2 promoter activity, affecting intracellular signaling pathways in a manner that mimics clonal anergy. We had shown previously that NFAT activates a transcriptional program, ensuing in immunological tolerance. In the present work, we have engineered lentiviral vectors expressing the HCV core to analyze the events, which unfold in the initial phase of HCV core-induced anergy. We show that genes initially described to be up-regulated by ionomycin-induced anergy in mice are also up-regulated in humans, not only by ionomycin but also by HCV core expression. We also show that HCV core is sufficient to cause NFAT nuclear translocation and a slow-down in cell-cycle progression, and using whole genome microarrays, we identify novel genes up-regulated in Jurkat cells expressing HCV core. The relevance of our results is highlighted by the presence of HCV in CD4 T cells from HCV chronically infected patients.
Subject(s)
Clonal Anergy , Hepatitis C Antigens/metabolism , NFATC Transcription Factors/metabolism , T-Lymphocytes/metabolism , Viral Core Proteins/metabolism , Animals , Cell Cycle , Cell Proliferation , Chronic Disease , Flow Cytometry , Fluorescent Antibody Technique , Gene Expression Profiling , Hepacivirus/genetics , Hepatitis C Antigens/genetics , Humans , Ionophores/pharmacology , Jurkat Cells , Kidney/cytology , Kidney/metabolism , Lentivirus/genetics , Mice , NFATC Transcription Factors/genetics , Oligonucleotide Array Sequence Analysis , Protein Transport , RNA, Viral/genetics , RNA, Viral/metabolism , Signal Transduction , T-Lymphocytes/pathology , T-Lymphocytes/virology , Viral Core Proteins/geneticsABSTRACT
Serotonin syndrome, which occurs as a result of enhanced serotonin concentration in the central nervous system, is a well-known adverse effect of serotonin-active medications. The concomitant use of antidepressant drugs associated with lithium as a co-adjuvant seems to increase the risk of this adverse reaction. We report a case of the serotonin syndrome during treatment with lithium and venlafaxine, an antidepressant with a dual selective re-uptake inhibition mechanism, and review the literature for similar cases. A 71-year-old woman developed serotonin syndrome while receiving treatment with moderate doses of lithium and venlafaxine for refractory depression. She had been taking higher doses of venlafaxine during the previous months with no significant secondary effects. Use of the Naranjo adverse drug reaction probability algorithm indicated a probable relationship between serotonin syndrome and treatment with lithium and venlafaxine.
Subject(s)
Antidepressive Agents, Second-Generation/adverse effects , Cyclohexanols/adverse effects , Lithium Carbonate/adverse effects , Serotonin Syndrome/chemically induced , Aged , Antidepressive Agents, Second-Generation/therapeutic use , Cyclohexanols/therapeutic use , Depressive Disorder, Major/drug therapy , Drug Interactions , Female , Humans , Lithium Carbonate/therapeutic use , Venlafaxine HydrochlorideABSTRACT
BACKGROUND: The new local anesthetic IQB-9302 is an amide derivative bearing a cyclopropyl group, with remarkable long duration of action and relative low toxicity. In trying to characterize further its safety profile, the current study compared the hemodynamic effects of different concentrations of bupivacaine and IQB-9302 with saline. METHODS: Two groups of eight anesthetized Sprague-Dawley rats were given 0.1, 0.3, 1, 3, and 10 mg/kg of intravenous (i.v.) IQB-9302 or bupivacaine at 20-min intervals; control animals received saline only. Arterial blood pressure and heart rate were monitored during the following 20 min. RESULTS: Both bupivacaine and IQB-9302 reduced heart rate: for bupivacaine, -73.8 beats per min (bpm) (SD: 103.8) and -132.5 bpm (SD: 140.7) at 1 and 3 mg/kg, respectively; for IQB-9302, the reduction amounted to -40.8 bpm (SD: 14.2) and -113.5 bpm (SD: 94.2) at 1 and 3 mg/kg, respectively (baseline range, 318.7-438.2 bpm). The two drugs also produced a comparable increase in the mean arterial blood pressure; bupivacaine increased it by 8.7 mmHg (SD: 6.6) and 12.6 mmHg (SD: 15.4) at 1 and 3 mg/kg, respectively, and IQB-9302, 18.7 mmHg (SD: 21.1) and 20.7 mmHg (SD: 20.5) at 1 and 3 mg/kg, respectively (baseline range, 47.4-134.1 mmHg). All rats treated with 10 mg/kg of either drug died after a drop in heart rate and mean arterial blood pressure. CONCLUSION: IQB-9302 had hemodynamic effects similar to those of bupivacaine in anesthetized rats. The clinical relevance of these effects warrants further investigation.
Subject(s)
Anesthesia, General , Anesthetics, Local/pharmacology , Bupivacaine/pharmacology , Hemodynamics/drug effects , Piperidines/pharmacology , Analysis of Variance , Anesthetics, Local/administration & dosage , Anesthetics, Local/adverse effects , Animals , Blood Pressure/drug effects , Bupivacaine/administration & dosage , Bupivacaine/adverse effects , Dose-Response Relationship, Drug , Female , Heart Rate/drug effects , Infusions, Intravenous , Male , Models, Animal , Piperidines/administration & dosage , Piperidines/adverse effects , Rats , Rats, Sprague-Dawley , Statistics, Nonparametric , Time FactorsABSTRACT
La claritromicina es un antibiótico macrólido utilizado de forma muy frecuente en el tratamiento de las infecciones respiratorias. El objetivo de este trabajo fue evaluar su eficacia en el tratamiento de las infecciones de vías respiratorias bajas. Para ello se han llevado a cabo varios metaanálisis de los ensayos clínicos realizados de forma comparativa con los antibióticos más empleados en este tipo de infecciones, como cefalosporinas, amoxicilina-ácido clavulánico, eritromicina y azitromicina. En cuanto a su eficacia, cuando evaluamos el tratamiento de las infecciones de vías respiratorias bajas, la claritromicina resultó ser más eficaz que las cefalosporinas (OR = 1,43; IC95 por ciento = 1,09-1,86) y casi se puede afirmar que respecto de la amoxicilina-ácido clavulánico (OR = 1,58; IC95 por ciento = 0,92-2,70); sin embargo, la eficacia fue similar en comparación con la azitromicina (OR = 0,57; IC95 por ciento = 0,19-1,68). En el cuarto metaanálisis realizado se comparó la claritromicina con la eritromicina en el tratamiento de la neumonía y prácticamente se puede afirmar que la eficacia fue superior con claritromicina (OR = 1,46; IC95 por ciento = 0,97-2,2). En cuanto a los metaanálisis efectuados para evaluar la seguridad de la claritromicina en las mismas enfermedades y con los mismos fármacos para los que se analizó la eficacia, se observó que la incidencia de efectos adversos era muy similar en comparación con amoxicilina-ácido clavulánico y azitromicina, algo menor respecto a la eritromicina y superior respecto a las cefalosporinas. En conclusión, estos metaanálisis demuestran que la claritromicina es un antibiótico eficaz y seguro en el tratamiento de las infecciones de vías respiratorias bajas. Además, actualmente existe una nueva formulación de administración en una dosis diaria que mejora el cumplimiento terapéutico, por lo que la claritromicina es un antibiótico de primera elección para el tratamiento de este tipo de infecciones (AU)
Subject(s)
Humans , Respiratory Tract Infections , Clarithromycin , Anti-Bacterial AgentsABSTRACT
El objetivo de este trabajo es evaluar la eficacia de la claritromicina respeto a otros antibióticos comúnmente empleados en las infecciones de vías respiratorias altas. Se han realizado varios metaanálisis de los ensayos clínicos comparativos encontrados en una búsqueda bibliográfica. En cuanto a eficacia, no existían diferencias significativas en la comparación de claritromicina con amoxicilina-ácido clavulánico en las infecciones de vías respiratorias altas, ni con cefalosporinas, amoxicilina y amoxicilina-ácido clavulánico en la otitis media, ni con respecto a penicilina oral en la faringoamigdalitis estreptocócica. La claritromicina era más eficaz que los betalactámicos en la sinusitis (OR: 1,27, IC95 por ciento: 1,01-1,61 en el análisis por intención de tratar). La eficacia era algo superior con claritromicina que con azitromicina, pero sólo alcanzaba significación estadística en el análisis por protocolo. El análisis conjunto de los 33 estudios clínicos incluidos mostraba un pequeño beneficio a favor de claritromicina que alcanzaba significación estadística en el modelo de efectos fijos (OR: 1,12, IC95 por ciento: 1,01-1,25). En cuanto a seguridad, la incidencia de efectos adversos fue significativamente más baja con claritromicina que con amoxicilina y amoxicilinaácido clavulánico. No se encontraron diferencias significativas en las comparaciones con cefalosporinas, azitromicina y betalactámicos, pero la incidencia de efectos adversos fue más alta con claritromicina que con penicilina oral en el tratamiento de la faringoamigdalitis estreptocócica. En general todos los fármacos comparados son bien tolerados; el número de abandonos por efectos adversos fue muy bajo: 2,2 por ciento con claritromicina y 2,5 por ciento con los otros antimicrobianos. En conclusión, la claritromicina resulta eficaz y segura en el tratamiento de las infecciones de vías respiratorias altas, y su nueva formulación de administración en dosis única diaria mejora el cumplimiento terapéutico (AU)
Subject(s)
Humans , Clarithromycin , Respiratory Tract Infections , Anti-Bacterial AgentsABSTRACT
Anticholinergic agents have proved to be of particular value in the treatment of COPD, as vagal cholinergic tone appears to be the only reversible component of airway narrowing, opposite to what happens in asthma. Anticholinergics block muscarinic receptors on airway smooth muscle an submucosal gland cells. Three subtypes of muscarinic receptors have been demonstrated in human airways. M1 receptors in parasympathetic ganglia facilitate cholinergic neurotransmission. M3 receptors on airway smooth muscle cells and glands mediate bronchoconstriction and mucus secretion. M2 receptors at cholinergic nerve endings inhibit the release of acetylcholine and therefore act as feedback inhibitory receptors (autoreceptors). Ipratropium bromide is a non-selective muscarinic antagonist and therefore blocks M1, M2 and M3 receptors. Tiotropium is a novel, potent, and long-lasting muscarinic antagonist that has a kinetic selectivity for M1 and M3 receptors because it dissociated very quickly from M2 receptors. Once-daily inhaled tiotropium is a safe and effective bronchodilator useful as a first-line maintenance therapy in COPD.
Subject(s)
Bronchi/physiology , Muscle, Smooth/physiology , Pulmonary Disease, Chronic Obstructive/metabolism , Receptors, Muscarinic/physiology , Bronchi/drug effects , Bronchodilator Agents/therapeutic use , Humans , Ipratropium/therapeutic use , Muscarinic Antagonists/therapeutic use , Muscle, Smooth/drug effects , Pulmonary Disease, Chronic Obstructive/drug therapy , Receptor, Muscarinic M1 , Receptor, Muscarinic M2 , Receptor, Muscarinic M3 , Scopolamine Derivatives/therapeutic use , Tiotropium BromideABSTRACT
Los fármacos anticolinérgicos son especialmente útiles en el tratamiento de la EPOC ya que el tono colinérgico vagal parece ser el único componente reversible del estrechamiento de la vía aérea en esta enfermedad, a diferencia de lo que ocurre en el asma. Estos fármacos bloquean los receptores muscarínicos del músculo liso de las vías aéreas y de las glándulas submucosas. En las vías aéreas en humanos se han identificado 3 subtipos de receptores muscarínicos que parecen tener diferentes funciones fisiológicas. Los receptores M1 de los ganglios parasimpáticos facilitan la neurotransmisión colinérgica. Los receptores M3 del músculo liso de las vías aéreas y de las glándulas median la broncoconstricción y la secreción de moco. Los receptores M2 de las terminaciones nerviosas colinérgicas inhiben la liberación de acetilcolina y por tanto actúan como retroalimentación inhibidora (autorreceptores). El bromuro de ipratropio es un antagonista muscarínico no selectivo que bloquea los receptores M1, M2 y M3. El tiotropio es un antagonista muscarínico nuevo, potente y de larga duración que posee selectividad cinética por los receptores M1 y M3 ya que se disocia rápidamente de los receptores M2. El tiotropio administrado una vez al día por vía inhalatoria es un broncodilatador seguro y eficaz, útil como tratamiento de mantenimiento de primera línea para la EPOC. (AU)
Subject(s)
Humans , Scopolamine Derivatives , Muscarinic Antagonists , Ipratropium , Muscle, Smooth , Receptors, Muscarinic , Receptor, Muscarinic M3 , Pulmonary Disease, Chronic Obstructive , Receptor, Muscarinic M2 , Receptor, Muscarinic M1 , Bronchi , Bronchodilator AgentsABSTRACT
Clarithromycin is a macrolide antibiotic commonly used for the treatment of respiratory infections. The aim of this study was to assess its effectiveness for the treatment of lower respiratory tract infections. A number of meta-analyses of clinical trials comparing clarithromycin to the antibiotics most frequently used in the treatment of lower respiratory tract infections, such as cephalosporins, amoxicillin-clavulanic acid, erythromycin and azithromycin, have been performed. Clarithromycin's effectiveness for the treatment of lower respiratory tract infections was better than that for cephalosporins (OR = 1.43; 95% CI = 1.09-1.86) and, although not to the same extent, that for amoxicillin-clavulanic acid (OR = 1.58; 95% CI = 0.92-2.70); however, the efficacy was only similar to that shown for azithromycin (OR = 0.57; 95% CI = 0.19-1.68). The fourth meta-analysis compared the effectiveness of clarithromycin to that of erythromycin for the treatment of pneumonia and showed a superior odds ratio in favor of clarithromycin (OR = 1.46; 95% CI = 0.97-2.2). Meta-analyses comparing clarithromycin's safety to that of the same drugs in the same conditions used in the assessment of effectiveness showed a similar incidence of adverse events compared to amoxicillin-clavulanic acid, and azithromycin, a slightly lower incidence compared to erythromycin, and a slightly higher incidence compared to cephalosporins. In conclusion, these meta-analyses show that clarithromycin is an effective and safe antibiotic for the treatment of lower respiratory tract infections. Furthermore, a new once-daily dose formulation with a positive impact on therapeutic compliance is currently available, making clarithromycin a first-line treatment for lower respiratory tract infections.
Subject(s)
Anti-Bacterial Agents/therapeutic use , Clarithromycin/therapeutic use , Respiratory Tract Infections/drug therapy , Clinical Trials as Topic , HumansABSTRACT
The goal of this meta-analysis was to evaluate the effectiveness of clarithromycin versus most commonly used treatments for upper respiratory infections. We performed a systematic review of comparative clinical trials found in the literature. Regarding effectiveness, no significant differences were found in comparisons between clarithromycin and amoxicillin-clavulanic acid for upper respiratory infections, nor for cephalosporins, amoxicillin or amoxicillin-clavulanic acid for otitis media, nor oral penicillin for classic streptococcal tonsillitis. Clarithromycin was more effective than betalactam antibiotics for sinusitis (OR: 1.27, 95% CI: 1.01-1.61 in intent-to-treat analysis). The effectiveness of clarithromycin was better than that for azithromycin, but only reached statistical significance in the per-protocol analysis. The global analysis including all 33 clinical trials showed a small benefit for clarithromycin reaching statistical significance in the fixed-effects model (OR: 1.12, 95% CI: 1.01-1.25). Regarding safety, the incidence of adverse events was significantly lower for clarithromycin compared to amoxicillin and amoxicillin-clavulanic acid. No differences were found when comparing adverse events due to cephalosporins, azithromycin and betalactam antibiotics, but the incidence of adverse events for clarithromycin was higher compared to that of oral penicillin for streptococcal tonsillitis treatment. Overall, all the compared drugs were well tolerated; discontinuations due to adverse events were very low: 2.2% for clarithromycin treatment and 2.5% for the other antibiotics. It was concluded that clarithromycin is an effective and safe treatment for upper respiratory infection, and its new formulation in a single daily dose may improve therapeutic compliance.
Subject(s)
Anti-Bacterial Agents/therapeutic use , Clarithromycin/therapeutic use , Respiratory Tract Infections/drug therapy , Clinical Trials as Topic , HumansABSTRACT
UNLABELLED: We evaluated the duration of sensory anesthesia after blockade of the ulnar nerve of IQB-9302, a new local amide anesthetic, compared with bupivacaine. A double-blinded, randomized, cross-over study in 12 healthy volunteers aged 18 to 35 yr was performed. Three milliliters of 0.25% IQB-9302 was administered in one wrist and bupivacaine in the other. A week later, the blocks were repeated with a concentration of 0.5%. These concentrations were chosen because they seemed to be equipotent in previous studies. The duration of sensory anesthesia was the main variable measured; secondary outcomes were motor block, time to onset, and time to recovery from block. The duration of sensory block was similar for IQB-9302 and bupivacaine at a concentration of 0.25%; median and range: 409 min (0-800 min) for IQB-9302 and 258 min (0-665 min) for bupivacaine (95% confidence interval for the difference from -47 to 545, P = 0.82, Wilcoxon's test). The results with 0.5% were: 525 min (440-735 min) and 690 min (365-1098 min), respectively (P = 0.026). There were no significant differences in the other variables measured. No important adverse reactions were seen. We conclude that IQB-9302 is an effective new local anesthetic for blockade of ulnar nerve at the concentrations tested. IMPLICATIONS: IQB-9302 is a new local anesthetic that has shown a long duration of action and low cardiovascular toxicity in preclinical studies. We report the results of a phase I clinical trial to compare this new drug with bupivacaine for ulnar nerve block.
Subject(s)
Anesthetics, Local , Bupivacaine , Nerve Block/methods , Piperidines , Ulnar Nerve/drug effects , Adolescent , Adult , Anesthetics, Local/adverse effects , Bupivacaine/adverse effects , Cross-Over Studies , Dose-Response Relationship, Drug , Double-Blind Method , Humans , Male , Piperidines/adverse effects , Skin Temperature/drug effectsABSTRACT
El sistema renina-angiotensina desempeña un papel fundamental en la fisiopatología de la hipertensión arterial. El eprosartán es un antagonista de los receptores de angiotensina de nueva generación que bloquea de forma selectiva los receptores de la angiotensina II del subtipo 1, tanto postsinápticos (vasculares) como presinápticos (neuronales), por lo que además disminuye la actividad simpática. Se elimina por vía biliar y renal y habitualmente no es necesario ajustar la dosis inicial en pacientes con insuficiencia hepática o renal. Como en su metabolismo no interviene el citocromo P450, es poco probable que produzca interacciones con otros fármacos, lo que favorece su utilización en terapia combinada y en pacientes polimedicados. Los resultados de varios ensayos clínicos ha demostrado que eprosartán (habitualmente 400-800 mg/día como una dosis o dividido en dos dosis) posee una eficacia antihipertensiva superior al placebo y al menos tan buena como enalapril o losartán. Es un fármaco bien tolerado y a diferencia del enalapril no produce tos. También se ha demostrado que es eficaz y seguro en pacientes mayores de 65 años (AU)
Subject(s)
Humans , Imidazoles/therapeutic use , Antihypertensive Agents/therapeutic use , Receptors, Angiotensin/antagonists & inhibitors , Hypertension/drug therapy , Imidazoles/pharmacokinetics , Imidazoles/pharmacology , Antihypertensive Agents/pharmacokinetics , Antihypertensive Agents/pharmacology , Renin-Angiotensin System/physiology , Treatment OutcomeABSTRACT
PURPOSE: To study the prevalence of altered eating behaviors or eating disorder-related behaviors among adolescents of normal weight that do not fulfill criteria for anorexia nervosa and bulimia nervosa. METHOD: Cross-sectional study by means of a self-completed questionnaire (School of Nutrition of Granada, Spain) and measurement of weight and height in a population of 491 schoolchildren aged 14-18 years. The statistical inferences and estimation of risk are based on comparison of proportions and means test, and the relative inequality of prevalences. RESULTS: Of 491 adolescents of normal weight, 9% (females 2:1) were following diets; 42% presented "recurrent episodes of binging" with the sensation of loss of self-control; and 41%% avoided specific types of food. Overall, 46.2% presented altered eating behavior. Factors significantly associated with this were the occurrence of periods of food abstinence and the use of purgatives [confidence interval 95% (CI 95%) prevalence ratio (PR) 1.41-2.02]. Compensatory behaviors were present in 33% of the adolescents, predominantly in females (CI 95% PR 1.79-3.07). The prevalences of abnormal eating behaviors were 16.3% for those related to anorexia (A-RB) and 17.1% for those related to bulimia (B-RB), with a clear predominance of females (2:1) and public education. There seems to be a greater aesthetic concern among those with B-RB and more worry about weight among those with A-RB. CONCLUSIONS: A high proportion of adolescents with abnormal eating behaviors and an altered perception of body fat may currently be diagnosed as having atypical eating disorder" (Diagnostic and Statistical Manual of Mental Disorders, Fourth Revision) considering that their body mass index was within normal range.
Subject(s)
Adolescent Behavior , Feeding Behavior/psychology , Feeding and Eating Disorders/psychology , Adolescent , Analysis of Variance , Body Image , Cathartics/administration & dosage , Cross-Sectional Studies , Female , Humans , Male , Reference Values , Self Concept , Spain/epidemiology , Statistics, Nonparametric , Surveys and QuestionnairesABSTRACT
We established primary cultures of human pheochromocytoma chromaffin cells. We then tried to find what mechanism of their secretory apparatus could be altered to produce the massive release of catecholamines into the circulation and the subsequent hypertensive crisis observed in patients suffering this type of tumor. Their whole-cell Ca2+ channel currents could be pharmacologically separated into components similar to those found in normal human adrenal chromaffin cells: 20% L-type, 30% N-type, and 50% P/Q-type Ca2+ channels. However, modulation of the channels by exogenous or endogenous ATP and opioids, via a G-protein membrane-delimited pathway, was deeply altered; some cells having no modulation or very little modulation alternated with others having normal modulation. This may be the cause of the uncontrolled secretory response, measured amperometrically at the single-cell level. Some cells secreted for long time periods and were insensitive to nifedipine (L-type channel blocker) or to omega-conotoxin MVIIC (N/P/Q-type channel blocker), while others were highly sensitive to nifedipine and partially sensitive to omega-conotoxin MVIIC. Alteration of the autocrine/paracrine modulation of Ca2+ channels may lead to indiscriminate Ca2+ entry and exacerbate catecholamine release responses in human pheochromocytoma cells.
Subject(s)
Adrenal Gland Neoplasms/physiopathology , Calcium Channels/metabolism , Chromaffin Cells/physiology , Exocytosis/physiology , Pheochromocytoma/physiopathology , Adenosine Triphosphate/pharmacology , Adrenal Gland Neoplasms/pathology , Adult , Barium/physiology , Calcium Channels/physiology , Chromaffin Cells/metabolism , Dopamine beta-Hydroxylase/metabolism , Electric Conductivity , Enkephalin, Ala(2)-MePhe(4)-Gly(5)-/pharmacology , Enkephalin, D-Penicillamine (2,5)-/pharmacology , Epinephrine/blood , Humans , Immunohistochemistry , Male , Middle Aged , Norepinephrine/blood , Phenylethanolamine N-Methyltransferase/metabolism , Pheochromocytoma/pathology , Tumor Cells, CulturedABSTRACT
INTRODUCTION: Citicoline has a neuroprotector effect since it reduces the lesions of nerve membranes, by increase in the synthesis of phospholipids, and reduces the levels of free fatty acids. In this study we review the existing data on the efficacy of citicoline in the treatment of acute ischemic cerebrovascular disease and its sequelae, both in animals and in clinical trials involving patients. DEVELOPMENT: In various animal models citicoline reduces the volume of cerebral infarction and neurological sequelae and also potentiates the effects of other neuroprotector drugs. On analysis of the literature, we found six randomised clinical trials, double-blind and placebo-controlled in which the effect of citicoline was evaluated in patients who had acute ischemic cerebrovascular accidents. In all of these it was found that citicoline reduced the neurological sequelae. The finding of a broad therapeutic window (24-48 hours) gives this an advantage over the fibrinolytic agents, which have to be given within the first three to six hours. In further controlled trials carried out in patients with sequelae of cerebrovascular disease different degrees of neurological improvement were found, although studies of greater duration are required to see improvement in a longer term. CONCLUSIONS: With the data available, we may affirm that citicoline is a safe, effective drug, although clinical trials are still underway in larger populations of patients. In these trials not only the neurological state but also the area of infarction are assessed to confirm their efficacy.
Subject(s)
Brain Ischemia/drug therapy , Cytidine Diphosphate Choline/therapeutic use , Nootropic Agents/therapeutic use , Clinical Trials as Topic , HumansABSTRACT
Introducción y objetivo. La citicolina posee efecto neuroprotector porque reduce la lesión de las membranas neuronales, a través del aumento de la síntesis de fosfolípidos, y disminuye los niveles de ácidos grasos libres. En este trabajo se revisan los datos existentes sobre la eficacia de la citicolina en el tratamiento de la enfermedad cerebrovascular isquémica aguda y sus secuelas, tanto en animales como en ensayos clínicos con pacientes. Desarrollo. En distintos modelos animales, la citicolina disminuye el volumen del infarto cerebral y las secuelas neurológicas y, además, potencia el efecto producido por otros fármacos neuroprotectores. Tras el análisis de la literatura, hemos encontrado seis ensayos clínicos aleatorizados, doble ciegos y controlados con placebo, en los que se evalúa el efecto de la citicolina en pacientes que han sufrido un accidente cerebrovascular agudo isquémico.En todos ellos se ha encontrado que la citicolina disminuye las secuelas neurológicas. El hallazgo de una ventana terapéutica amplia (24-48 horas) supone una ventaja frente a los fibrinolíticos, que deben administrarse dentro de las primeras tres a seis horas. En nueve ensayos controlados realizados en pacientes con secuelas de enfermedad cerebrovascular se han apreciado diversos grados de mejoría neurológica, aunque se requieren estudios más prolongados para ver mejoría a más largo plazo. Conclusiones. Con los datos disponibles podemos afirmar que la citicolina es un fármaco seguro y eficaz, si bien se siguen realizando ensayos clínicos con amplias poblaciones de pacientes y en los cuales se evalúa no sólo el cuadro neurológico, sino también el área infartada, para corroborar su eficacia (AU)
Subject(s)
Humans , Nootropic Agents/therapeutic use , Cytidine Diphosphate Choline/therapeutic use , Brain Ischemia/drug therapy , Clinical Trials as TopicABSTRACT
OBJECTIVES: To identify the individual and occupational factors that are predictors for low back pain among the employees of a university hospital in southern Spain. METHODS: A transverse study was conducted in which the population used was the hospital employees who volunteered to participate. The information was obtained by using a questionnaire, which included demographic and anthropometric variables, habits, characteristics of the work done, and of any pain experienced. The mental health condition of subjects was measured using the GHQ-28, using a score of > or = 6 as the cut-off point. To study the variables associated with pain, crude odds ratios (ORs) were calculated (+/- 95% CI) and adjusted according to a logistic regression model. RESULTS: One thousand one hundred and four subjects participated in the study but only 890 of these completed the questionnaire in full (rate of response, 35.7% of total employees). The population studied was notable for the high proportion of women, for subjects > 41 years of age, and subjects who undertook little or no physical exercise. In addition, according to the GHQ-28 test, 29.9% of the total were 'probable psychiatric cases'. The crude ORs were high in all the occupational categories in comparison with the doctors, with the exception of the maintenance, cleaning, and catering group. They were also higher among women, among subjects with poor mental health, and among women with one or more children. The adjusted ORs showed that having a GHQ-28 score of > or = 6, and belonging to the auxiliary technician category, were independent risk factors for suffering low back pain. Being older than 41 years and in temporary employment were protective variables. CONCLUSIONS: The presence of probable mental illness is the variable most strongly associated with the presence of low back pain in the population studied. Its diagnostic confirmation and appropriate treatment could contribute to reducing the prevalence of vertebral pains in this occupational group.
Subject(s)
Low Back Pain/epidemiology , Occupational Diseases/epidemiology , Personnel, Hospital , Adult , Female , Hospitals, University , Humans , Logistic Models , Low Back Pain/psychology , Male , Occupational Diseases/psychology , Odds Ratio , Risk Factors , Spain/epidemiology , WorkforceABSTRACT
Mitochondrial dysfunction has been implicated in a number of neurodegenerative diseases, such as ischemia and Parkinson's disease. We present here a method that allows the rapid quantification of interventions, aimed at inhibiting the effect of mitochondrial membrane potential uncouplers, based on the ratioing properties of the fluorescent probe 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolcarbocyanine iodide (JC-1), by using currently available 96-well fluorescent plate readers. A method is presented for evaluation of cross-talk between the two excitation/emission channels. Further characterization of the probe shows that the effect of plasma membrane potential changes on JC-1 fluorescence ratio are negligible, but that the signal is very sensitive to pH. One of the most exciting applications is the possibility to perform end-point measurements, thanks to the ratioing properties of the probe. The system is tested in different culture types with different mitochondrial uncouplers. As an example of a quantitative evaluation, we show that flunarizine is able to inhibit, dose-dependently, FCCP mediated JC-1 signal increase. The procedure is simple and allows for the fast screening of mitochondria-protective compounds.
Subject(s)
Benzimidazoles , Carbocyanines , Membrane Potentials/drug effects , Mitochondria/drug effects , Animals , Calcium Channel Blockers/pharmacology , Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone/pharmacology , Flunarizine/pharmacology , Membrane Potentials/physiology , Mitochondria/physiology , PC12 Cells , Rats , Uncoupling Agents/pharmacologyABSTRACT
BACKGROUND & AIMS: This study has investigated stimulus-secretion coupling of enterochromaffin cells by studying the cellular location and function of voltage-gated Ca(2+) channels within small intestinal crypts. METHODS: Digital fluorescence imaging and electrochemical detection were used to measure intracellular Ca(2+) responses and serotonin (5-hydroxytryptamine [5-HT]) secretion in intact crypts isolated from guinea pig and human duodenum. RESULTS: In fluo-3-loaded crypts, electrical depolarization with high K(+) solution increased cytosolic free [Ca(2+)] only in single cells subsequently identified by immunocytochemistry as enterochromaffin cells. In guinea pig enterochromaffin cells, the L-type Ca(2+) channel agonist FPL 64176 (3 micromol/L) did not change resting intracellular [Ca(2+)] but potentiated the depolarization-evoked increase in [Ca(2+)] (298 +/- 72 nmol/L) by 19 +/- 3-fold. In the majority of human enterochromaffin cells, FPL 64176 alone increased resting [Ca(2+)] by 423 +/- 171 nmol/L. Secretion studies in guinea pig crypts showed that high K(+) and FPL 64176 caused a 12-fold increase in 5-HT release. Noradrenaline caused increases in both enterochromaffin cell [Ca(2+)] and 5-HT release. CONCLUSIONS: Using this approach, we have found that in duodenal crypts, enterochromaffin cells, but not other epithelial cells, contain L-type voltage-gated Ca(2+) channels involved in regulating 5-HT secretion. These data have implications for the pharmacological control of intestinal disorders involving enterochromaffin cell dysfunction.
